Study Evaluating The Effects Of Neratinib After Adjuvant Trastuzumab In Women With Early Stage Breast Cancer (ExteNET)

• Sponsor: Puma Biotechnology, Inc.
• Information provided by (Responsible Party): Puma Biotechnology, Inc.

Study Description

Brief Summary:

The purpose of this study is to investigate whether neratinib can further reduce the risk of recurrence from previously diagnosed HER-2 positive breast cancer after adjuvant treatment with trastuzumab.

Condition or disease	Intervention/treatment	Phase
Breast Cancer	Drug: neratinib; Other: placebo	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 2840 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled Trial Of Neratinib (HKI-272) After Trastuzumab In Women With Early-Stage HER-2/Neu Overexpressed/Amplified Breast Cancer
• Actual Study Start Date: July 9, 2009
• Actual Primary Completion Date: August 21, 2014
• Estimated Study Completion Date: November 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Neratinib; 240 mg orally daily for one year	Drug: neratinib; Other Names: HKI-272; Nerlynx
Placebo Comparator: Placebo; orally daily for one year	Other: placebo

Outcome Measures

Primary Outcome Measures :

1. Invasive Disease-free Survival (iDFS) in Neratinib Arm Compared to Placebo Arm [ Time Frame: From randomization until time of event up to 2 years ]
   Invasive disease-free survival time is defined as the time from date of randomization until the first disease recurrence of the following events: invasive ipsilateral breast tumor recurrence, invasive contralateral breast cancer, local/regional invasive recurrence, distant recurrence and death from any cause.
2. Kaplan-Meier Estimates of Invasive Disease-free Survival (iDFS) at Year 2 by Treatment Arms [ Time Frame: From randomization until time of event up to 2 years ]

Secondary Outcome Measures :

1. Overall Survival (OS) [ Time Frame: From time of randomization to death ]
   Overall survival is defined as the time from randomization to death from any cause
2. Disease-free Survival Including Ductal Carcinoma in Situ (DFS-DCIS) in Neratinib Arm Compared to Placebo Arm [ Time Frame: From randomization until time of event up to 2 years ]
   Disease-free survival including DCIS time is defined as the time from date of randomization until the first occurrence of DCIS or an iDFS event (an iDFS event including invasive ipsilateral breast tumor recurrence, invasive contralateral breast cancer, local/regional invasive recurrence, or distant recurrence and death from any.
3. Kaplan-Meier Estimates of Disease-free Survival Including Ductal Carcinoma in Situ (DFS-DCIS) at Year 2 by Treatment Arms [ Time Frame: From randomization until time of event up to 2 years ]
4. Distant Disease-free Survival (DDFS) in Neratinib Arm Compared to Placebo Arm [ Time Frame: From randomization until time of event up to 2 years ]
   Distant disease-free survival time is defined as the time from date of randomization until the first occurrence of distant recurrence or death from any cause.
5. Kaplan-Meier Estimates of Distant Disease-free Survival (DDFS) at Year 2 by Treatment Arms [ Time Frame: From randomization until time of event up to 2 years ]
6. Time to Distant Recurrence (TTDR) in Neratinib Arm Compared to Placebo Arm [ Time Frame: From randomization until time of event up to 2 years ]
   Time to distant recurrence is defined as the time from date of randomization until the first occurrence of distant recurrence or death from breast cancer.
7. Kaplan-Meier Estimates of Time to Distant Recurrence (TTDR) Survival at Year 2 by Treatment Arms [ Time Frame: From randomization until time of event up to 2 years ]
8. Central Nervous System Recurrence in Neratinib Arm Compared to Placebo Arm [ Time Frame: From randomization until time of event up to 2 years ]
   CNS recurrence is defined as the time from randomization to CNS as the first distant recurrence. Competing events include distant recurrence at other sites as the first distant recurrence and death from any cause prior to distant recurrence.
9. Cumulative Incidence of Central Nervous System Recurrence (CNS) at Year 2 [ Time Frame: From randomization until time of event up to 2 years ]
   Cumulative incidence of Central Nervous System Recurrence (CNS) is estimated by Gray's method (Gray,1988).

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Stage II through IIIC HER-2/erbB-2 positive breast cancer with node positive disease.
• Been treated for early breast cancer with standard of care duration of trastuzumab.
• Could have been treated neoadjuvantly but have not reached pathologic complete response.

Exclusion Criteria:

• Positive clinical and radiologic assessments for local or regional recurrence of disease at the time of study entry.
• History of heart disease.
• Corrected QT (QTc) interval >0.45 seconds
• History of gastrointestinal disease with diarrhea as the major symptom.

Contacts and Locations

  Show 492 Study Locations

Sponsors and Collaborators

Puma Biotechnology, Inc.

Investigators

• Study Director: Clinical Development Chief Medical and Scientific Officer; Puma Biotechnology, Inc.

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Iwata H, Masuda N, Kim SB, Inoue K, Rai Y, Fujita T, Chiu J, Ohtani S, Takahashi M, Miyaki T, Lu YS, Xu B, Yap YS, Bustam A, Yao B, Zhang B, Bryce R, Chan A. Neratinib after trastuzumab-based adjuvant therapy in patients from Asia with early stage HER2-positive breast cancer. Future Oncol. 2019 May 29. doi: 10.2217/fon-2019-0143. [Epub ahead of print]

Chia SKL, Martin M, Holmes FA, Ejlertsen B, Delaloge S, Moy B, Iwata H, von Minckwitz G, Mansi J, Barrios CH, Gnant M, Tomašević Z, Denduluri N, Šeparović R, Kim SB, Jakobsen EH, Harvey V, Robert N, Smith J 2nd, Harker G, Zhang B, Eli LD, Ye Y, Lalani AS, Buyse M, Chan A. PIK3CA alterations and benefit with neratinib: analysis from the randomized, double-blind, placebo-controlled, phase III ExteNET trial. Breast Cancer Res. 2019 Mar 11;21(1):39. doi: 10.1186/s13058-019-1115-2.

Mortimer J, Di Palma J, Schmid K, Ye Y, Jahanzeb M. Patterns of occurrence and implications of neratinib-associated diarrhea in patients with HER2-positive breast cancer: analyses from the randomized phase III ExteNET trial. Breast Cancer Res. 2019 Feb 27;21(1):32. doi: 10.1186/s13058-019-1112-5.

Delaloge S, Cella D, Ye Y, Buyse M, Chan A, Barrios CH, Holmes FA, Mansi J, Iwata H, Ejlertsen B, Moy B, Chia SKL, Gnant M, Smichkoska S, Ciceniene A, Martinez N, Filipović S, Ben-Baruch NE, Joy AA, Langkjer ST, Senecal F, de Boer RH, Moran S, Yao B, Bryce R, Auerbach A, Fallowfield L, Martin M. Effects of neratinib on health-related quality of life in women with HER2-positive early-stage breast cancer: longitudinal analyses from the randomized phase III ExteNET trial. Ann Oncol. 2019 Apr 1;30(4):567-574. doi: 10.1093/annonc/mdz016.

Martin M, Holmes FA, Ejlertsen B, Delaloge S, Moy B, Iwata H, von Minckwitz G, Chia SKL, Mansi J, Barrios CH, Gnant M, Tomašević Z, Denduluri N, Šeparović R, Gokmen E, Bashford A, Ruiz Borrego M, Kim SB, Jakobsen EH, Ciceniene A, Inoue K, Overkamp F, Heijns JB, Armstrong AC, Link JS, Joy AA, Bryce R, Wong A, Moran S, Yao B, Xu F, Auerbach A, Buyse M, Chan A; ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1688-1700. doi: 10.1016/S1470-2045(17)30717-9. Epub 2017 Nov 13.

Chan A, Delaloge S, Holmes FA, Moy B, Iwata H, Harvey VJ, Robert NJ, Silovski T, Gokmen E, von Minckwitz G, Ejlertsen B, Chia SK, Mansi J, Barrios CH, Gnant M, Buyse M, Gore I, Smith J 2nd, Harker G, Masuda N, Petrakova K, Zotano AG, Iannotti N, Rodriguez G, Tassone P, Wong A, Bryce R, Ye Y, Yao B, Martin M; ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016 Mar;17(3):367-77. doi: 10.1016/S1470-2045(15)00551-3. Epub 2016 Feb 10.

• Responsible Party: Puma Biotechnology, Inc.
• ClinicalTrials.gov Identifier: NCT00878709 History of Changes
• Other Study ID Numbers: 3144A2-3004 / B1891004
• First Posted: April 9, 2009
• Results First Posted: October 9, 2017
• Last Update Posted: May 13, 2019
• Last Verified: May 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Puma Biotechnology, Inc.:

HER-2/erbB-2 positive breast cancer; breast cancer; adjuvant therapy; neratinib; HKI-272; Nerlynx; PB-272

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Trastuzumab; Antineoplastic Agents, Immunological; Antineoplastic Agents